Genetics of Vitiligo

Abstract

Abstract Vitiligo is an autoimmune disease that results in destruction of skin melanocytes and patches of white skin and hair. Family studies of vitiligo demonstrated that a strong, but complex genetic component underlies disease risk and that vitiligo often occurs with other autoimmune diseases, suggesting shared autoimmune susceptibility. Genome‐wide linkage and association studies have identified over 50 vitiligo susceptibility loci, with most loci harbouring genes involved in immune regulation, apoptosis or melanocyte function. The identified loci fit together in a model of melanocyte‐directed autoimmunity, and many loci are shared with other autoimmune diseases. Surprisingly, some genetic vitiligo susceptibility alleles are inversely associated with melanoma, suggesting that vitiligo may represent enhanced immune surveillance against melanoma. Genetic studies of vitiligo have greatly advanced understanding of vitiligo pathobiology and may additionally provide insights into melanoma and other autoimmune disease. Key Concepts Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Vitiligo heritability is approximately 80% in Caucasians, about two‐thirds attributable to common genetic variants and one‐third to rarer variation. Vitiligo risk in both familial and sporadic cases follows a polygenic additive model, principally involving common risk alleles as well as unknown environmental triggers. Over 50 loci have been genetically associated with vitiligo, principally in Caucasian populations, though several exhibit trans‐ethnic association with vitiligo in other populations. Most vitiligo‐associated loci encode components of the immune system or proteins involved in melanogenesis; some of the latter comprise vitiligo autoantigens. Together, these provide a possible framework for vitiligo pathogenesis. Vitiligo is epidemiologically associated with several other autoimmune diseases, and nearly half of vitiligo‐associated loci are also associated with these other diseases. Though the major histocompatibility complex ( MHC ) is associated with most of these diseases, in vitiligo principal MHC association appears to be regulatory rather than protein coding. Some loci that encode melanocyte proteins exhibit inverse association between vitiligo and melanoma and other skin cancers, suggesting that vitiligo may represent dysregulated immune surveillance against melanoma.